Why It Matters

We have no effective treatments for dementia, a huge health crisis facing the world. The annual cost of care in the United States alone could reach $1 trillion by 2050.

When he learned in 1995 that he had Alzheimer’s disease, William Utermohlen, an American artist living in London, immediately began work on an ambitious series of self-portraits. The resulting body of work serves as a unique artistic, medical, and personal record of one man’s struggle with dementia.
(See the self-portrait series in more detail here.)

Tangled Connections

In October 1986, one year after his grandmother Sadie died of dementia in a New York City nursing home, Barry Greenberg cloned a gene he thought would be key in the battle against Alzheimer’s disease. Ever since the German physician Alois Alzheimer first described the pathological hallmarks of his namesake disease in 1906, scientists have focused on two prominent physiological features that snarl the brains of dementia patients: plaques of the gummy protein amyloid beta, which build up outside brain cells, and hairy tangles of protein inside neurons (these tangles are now known to be misshapen versions of a normal protein called tau). Greenberg, then working at a West Coast startup called California Biotechnology, had found the gene for amyloid precursor protein, which tells the body how to make the protein that ends up as the amyloid plaques. He excitedly called his father with the good news, and his father replied, “That’s wonderful, son. Now what’s left to be done?”

A quarter-century later, after stops at five pharmaceutical companies and countless twists and turns in the research saga, Greenberg can tell the anecdote with a chuckle, but the larger story is no laughing matter. He has seen this emerging medical disaster as a bench scientist, as a pharmaceutical-­industry insider, and now as a coördinator of clinical research and drug development for an alliance of Canadian hospitals and memory clinics associated with the University of Toronto, which serve some 7,000 dementia patients a year. In a recent talk to a lay audience on Prince Edward Island, he spoke about his grandmother’s illness and then dropped the hammer. “The scope of the looming medical-care disaster,” he said, “is beyond comparison with anything that has been faced during the entire history of humanity.”

The latest global demographic analysis, from a World Health Organization report issued earlier this year, paints the dimensions of that slow-motion catastrophe in quick strokes. An estimated 36 million people worldwide currently suffer from dementia; experts predict the number will double, to approximately 70 million, by 2030 and triple by 2050. (China, India, and Latin America in particular face daunting medico-economic crises.) Since the prevalence of the disease doubles with every five-year age increment after 65, projections for 2050 put the total global population at risk for dementia (people 65 or older) at two billion. The calculus is as grim as it is simple: as more people live longer, more slide into dementia. Care for those patients currently costs $100 billion a year in the United States, with a projected cost over the next 40 years of $20 trillion; by 2050, the cost to U.S. society is projected to be $1 trillion a year.

An even more sobering perspective on the problem comes from a small unpublished pilot study that Granieri and her colleagues at Columbia recently undertook. They did a standard cognitive evaluation of every person 70 or older who was admitted to Allen Hospital for any reason—heart problems, pain, diabetes, breathing difficulties. The results stunned them. “In this hospital, of patients 70 years of age or older, 90 percent have cognitive impairment of some kind, which is much higher than we anticipated,” she says.

Not only is dementia distressingly widespread, but the complex overlap of symptoms and possible causes makes addressing the problem broader and trickier than just treating Alzheimer’s. The emerging reality, which has become increasingly apparent with better brain imaging, is that the majority of cases among the elderly are so-called “mixed dementias”; the cognitive impairment is due to a combination of vascular problems, such as mini-strokes in discrete parts of the brain, and the more classic Alzheimer’s pattern of amyloid plaques. Large-scale international studies in the past three years have shown, according to a recent scientific summary, that dementias caused by blood-vessel lesions in the brain, including vascular dementia and mixed dementia, “together comprise the most common forms of dementia at autopsy in community-based studies.”

Sharon Brangman, a physician who finished a term as chair of the board of the American Geriatrics Society earlier this year, especially welcomes the message that Alzheimer’s in particular, and dementia in general, is much more complex than the focused research of the last 20 years would suggest. “When you’ve lost something, and you’ve looked in all the obvious places and you still haven’t found it, you need to start looking in other places,” she says. “Not everyone with Alzheimer’s has the same clinical presentation, and there’s more to dementia than Alzheimer’s disease. We have a broad disease category that people can enter from multiple avenues. But we are attacking dementia now from only one narrow entry point. It’s going to be more complicated than that. Right now, we have a one-size-fits-all approach to dementia.”

In order to come up with more effective drugs, scientists need to understand exactly how each kind of dementia develops and how to attack that specific disease process. Much of the research has so far focused on Alzheimer’s disease. And yet the basic biology of even that most well-studied form of dementia remains fuzzy. Are the amyloid plaques the key pathological factor, as a large body of research suggests, or is it the thickets of aberrant proteins known as tau tangles, which appear in dementia patients after the plaques do? If amyloid leads to tau tangles, how are they related? Or, as an alternative hypothesis suggests, is dementia somehow connected to impaired processing of blood sugar? (This possibility was endorsed by the NIH’s recent decision to support a University of Washington clinical trial of a nasal insulin spray.) Or does the actual cause of Alzheimer’s have something to do with an imbalance of metal ions in brain cells, which is the animating idea behind advanced clinical trials by an Australian biotech company?

The persistence of so many hypotheses suggests that neither clear-cut evidence nor consensus for one theory of disease has yet emerged. “I think you have to continue to look at these hypotheses,” says Granieri, “but they are hypotheses, and [researchers] have to be honest about that.”